Role of toxins in inherited disease

A disease you are suffering today could be a result of your great-grandmother being exposed to an environmental toxin during pregnancy.

Researchers at Washington State University reached that remarkable conclusion after finding that environmental toxins can alter the activity of an animal's genes in a way that is transmitted through at least four generations after the exposure. Their discovery suggests that toxins may play a role in heritable diseases that were previously thought to be caused solely by genetic mutations. It also hints at a role for environmental impacts during evolution.

"It's a new way to think about disease," said Michael K. Skinner, director of the Center for Reproductive Biology. "We believe this phenomenon will be widespread and be a major factor in understanding how disease develops."

The work is reported in the June 3 issue of Science Magazine.

Skinner and a team of WSU researchers exposed pregnant rats to environmental toxins during the period that the sex of their offspring was being determined. The compounds – vinclozolin, a fungicide commonly used in vineyards, and methoxychlor, a pesticide that replaced DDT – are known as endocrine disruptors, synthetic chemicals that interfere with the normal functioning of reproductive hormones.

Skinner's group used higher levels of the toxins than are normally present in the environment, but their study raises concerns about the long-term impacts of such toxins on human and animal health. Further work will be needed to determine whether lower levels have similar effects.

Pregnant rats that were exposed to the endocrine disruptors produced male offspring with low sperm counts and low fertility. Those males were still able to produce offspring, however, and when they were mated with females that had not been exposed to the toxins, their male offspring had the same problems. The effect persisted through all generations tested, with more than 90 percent of the male offspring in each generation affected. While the impact on the first generation was not a surprise, the transgenerational impact was unexpected.

Scientists have long understood that genetic changes persist through generations, usually declining in frequency as the mutated form of a gene gets passed to some but not all of an animal's offspring. The current study shows the potential impact of so-called epigenetic changes.

Epigenetic inheritance refers to the transmission from parent to offspring of biological information that is not encoded in the DNA sequence. Instead, the information stems from small chemicals, such as methyl groups, that become attached to the DNA. In epigenetic transmission, the DNA sequences – the genes – remain the same, but the chemical modifications change the way the genes work. Epigenetic changes have been observed before, but they have not been seen to pass to later generations.

While this research focused on the impact of these changes on male reproduction, the results suggested that environmental influences could have multigenerational impacts on heritable diseases. According to Skinner, epigenetic changes might play a role in diseases such as breast cancer and prostate disease, whose frequency is increasing faster than would be expected if they were the result of genetic mutations alone.

The finding that an environmental toxin can permanently reprogram a heritable trait also may alter our concept of evolutionary biology. Traditional evolutionary theory maintains that the environment is primarily a backdrop on which selection takes place, and that differences between individuals arise from random mutations in the DNA. The work by Skinner and his group raises the possibility that environmental factors may play a much larger role in evolution than has been realized before. This research was supported in part by a grant to Skinner from the U.S. Environmental Protection Agency's STAR Program.